The present invention relates to the Peg3 gene and the finding that it is involved in thermoregulation, obesity and maternal behaviour, olfaction, male behaviour, apoptosis, cell survival and degeneration, and infectious diseases.
The Peg3 gene was identified in a screen for expression of imprinted genes in mice. Imprinted genes show an unusual pattern of expression as their expression is determined strictly by their parental origin. Peg3 shows imprinting, with the paternal copy of the gene being expressed in offspring while the maternal copy is silent. The gene expresses an mRNA of about 9 kb in size which encodes an unusual zinc finger protein with eleven widely spaced xe2x80x9cC2H2xe2x80x9d motifs and two groups of amino acid repeats. The predicted size of the protein is 1,572 amino acids. See Kuroiwa et al, (1996), Nature Genetics 12; 186-189. The sequence of Peg3 can be found in GenBank, accession number AF038939 (NCBI-REF 363877).
Peg3 is expressed early in development in somites, branchial arches and other mesodermal tissue. In adults it is expressed predominantly in the brain including the hypothalamus medial preoptic area, amygdala as well as the olfactory bulb. It is also expressed in few other adult tissues such as the adrenal gland. The function of the gene is unknown, although in Kuroiwa et al, ibid, it is noted that the gene maps to a region of murine chromosome 7 which is syntenic with the human chromosomal location for genes associated with myotonic dystrophy and tumour suppression.
We have developed a transgenic mouse model in which we have disrupted the Peg3 gene. We have observed a number of surprising phenotypic changes, particularly obesity, lower core temperature, impaired maternal behaviour, abnormal male behaviour, smaller body size at birth and reduction in specific neurons in the hypothalamus. Moreover, obesity was found to develop in the mice despite a food intake lower than that of control animals. These findings suggest a role of Peg3 in the regulation of body weight and temperature, and provide a model system in which therapies for treatment of obesity, metabolic imbalances, growth regulation and behaviour may be studied.
The present invention thus provides a transgenic non-human animal, particularly a rodent, which comprises an inactive copy of the Peg3 gene.
The invention further provides a method of testing a putative modulator of body weight which comprises administering said putative modulator to an animal according to the invention and determining the effect of the putative modulator on body metabolism.
In an additional aspect, the invention also provides a method of testing a putative modulator of behaviour which comprises administering said putative modulator to an animal according to the invention and determining the effect of the putative modulator on behaviour.
The discovery of the function of the Peg3 gene allows the search for other genes involved in metabolic regulation, and thus the invention also provides a method for screening for genes associated with the regulation of body weight or temperature, which method comprises providing a Peg3 protein, bringing said protein into contact with other cellular proteins, and determining to which cellular proteins the Peg3 protein is able to bind. Such genes may be isolated and this forms a further aspect of the invention.
The role of Peg3 in mice allows the determination of a PEG3 genotype in humans with a phenotypic disorder associated with obesity or thermoregulation, by a method forming a further aspect of the invention. This method comprises:
providing nucleic acid from a group of obese patients and a control group of non-obese patients;
analysing said nucleic acid; and
determining one or more features of said nucleic acid associated with the obese phenotype.
An analogous method may be performed at the protein level, using antibodies to determine epitopes of PEG3 which differ between groups, either in the relative strength of binding or in their presence or absence.
The differences in protein epitopes or genotype determined by such screening may be utilized to provide a method of testing an individual""s susceptibility to obesity or a thermoregulatory disorder which comprises analysing the nucleic acid of said individual for one or more features of the PEG3 gene associated obesity or thermoregulatory disorders.
As used herein, xe2x80x9ccomprise(s)xe2x80x9d and xe2x80x9ccomprisingxe2x80x9d are to be interpreted as xe2x80x9cinclude(s) and xe2x80x9cincludingxe2x80x9d.